Table_1_Case Report: Systemic Treatment and Serial Genomic Sequencing of Metastatic Prostate Adenocarcinoma Progressing to Small Cell Carcinoma.xlsx

Small cell carcinoma (SCC)/neuroendocrine prostate cancer (NEPC) is a rare and highly aggressive subtype of prostate cancer associated with an AR(androgen receptor)-null phenotype and visceral metastases. This study presents a 44-year-old man originally diagnosed with metastatic hormone-sensitive prostatic adenocarcinoma. After 6-month androgen deprivation therapy (ADT) combined with docetaxel, the patient developed paraplegia. Laminectomy was performed, and a thoracic vertebral biopsy revealed neuroendocrine differentiation and mixed adenocarcinoma. The patient developed liver metastases and experienced stable disease for 4 months following etoposide combined with cisplatin and pembrolizumab. Seminal vesicle biopsy after chemotherapy revealed small-cell cancer. The prostate biopsy specimen also indicated pure SCC. We witnessed the dynamic evolution from pure adenocarcinoma to fully differentiated SCC, leading to obstruction and death. In addition, whole-exome sequencing was performed on both biopsy specimens of the thoracic vertebra at the beginning of castration resistance and that of seminal vesicle after multiple lines of treatment failure. Utilizing phylogenetic reconstruction, we observed that both samples shared a common ancestor clone harboring aberrations in the TP53, RB1, and NF2 genes. We also discovered that driver events in the private subclones of both samples, such as alterations in CDC27 and RUNX1, might have played a significant role in tumor progression or even neuroendocrine differentiation. Tumor biopsy and IHC assessment must be repeated at different stages of progression, because of intrapatient spatial and temporal heterogeneity of adenocarcinoma versus SCC/NEPC. Although, typical treatments including ADT, docetaxel, etoposide, cisplatin, and pembrolizumab provided temporary response, the patient still had a poor prognosis.

小细胞癌（SCC）/神经内分泌前列腺癌（NEPC）是一种罕见且高度侵袭的前列腺癌亚型，与AR（雄激素受体）缺失表型和内脏转移相关。本研究介绍了一位44岁男性，最初被诊断为转移性激素敏感性前列腺腺癌。在经过6个月的雄激素剥夺治疗（ADT）和多西他赛联合治疗后，患者出现了截瘫。行椎板切除术，胸椎活检发现神经内分泌分化和混合腺癌。患者出现肝转移，并在依托泊苷联合顺铂和派姆单抗治疗4个月后疾病稳定。化疗后的精囊活检揭示了小细胞癌。前列腺活检标本也表明为纯小细胞癌。我们见证了从纯腺癌到完全分化的小细胞癌的动态演变，最终导致梗阻和死亡。此外，在去势抵抗的早期和多次治疗失败后精囊活检的样本上进行了全外显子组测序。利用系统发育重建，我们发现两个样本共享一个具有TP53、RB1和NF2基因突变的共同祖先克隆。我们还发现，两个样本的私有亚克隆中的驱动事件，如CDC27和RUNX1的改变，可能在肿瘤进展或甚至神经内分泌分化中发挥了重要作用。由于腺癌与SCC/NEPC在患者内部空间和时间异质性方面，肿瘤活检和免疫组化评估必须在进展的不同阶段重复进行。尽管典型的治疗方法，包括ADT、多西他赛、依托泊苷、顺铂和派姆单抗提供了暂时的响应，但患者的预后仍然不佳。